Composition comprising a combination of dha and epa for administration prior to commencement of chemotherapy

ABSTRACT

The invention relates to a composition comprising a combination of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The composition can be used for enhancing the activity of chemotherapy or radiotherapy and/or in the prevention or reduction of side effects caused by the chemotherapy or radiotherapy in a patient ill with cancer, the composition being intended for administration to the patient prior to the commencement of a cycle of chemotherapy or radiotherapy.

FIELD OF THE INVENTION

The present invention relates to the use of an omega-3 fattyacid-comprising composition for administration to cancer patients priorto the start of a cycle of chemotherapy or radiation therapy. Theadministration of the composition improves the efficacy of the therapy.Adverse effects of the therapy are prevented or attenuated by theadministration of the therapy.

BACKGROUND OF THE INVENTION

Cancers are one of the most common causes of death worldwide. In thecase of women, the most common cancers are breast cancer, lung cancerand colorectal cancer. Particularly common in men is the development ofprostate cancer, lung cancer and colorectal cancer (Jemal et al. 2009;CA Cancer J Clin; 59(4): 225-49). Common to all cancers are changes inthe cell leading to uncontrolled growth thereof.

Depending on the nature and location of the tumor and depending on thedisease stage, the cancer is treated by surgical removal of the tumor,chemotherapy, radiation therapy, immunotherapy or further so-calledtargeted therapy forms, which for example comprise treatment withmonoclonal antibodies. In principle, it is possible to applychemotherapy and radiation therapy as the sole therapy. However,depending on the disease stage of the patient, a plurality of therapyforms are often combined. For instance, a tumor is frequently firstremoved by surgical means and chemotherapy is then applied in order tokill any cancer cells remaining in the body. Radiation therapy can, forexample, be used for first achieving shrinkage of the tumor,facilitating the subsequent surgical removal of the tumor. A combinationof chemotherapy and radiation therapy (“radiochemotherapy”) is used,inter alia, in the treatment of tumors of the rectum, of the cervix, ofthe lungs, of the breasts, of the esophagus and in head and neck tumors.

Despite improved therapy options for cancer patients, the disease is, ina multiplicity of cases, not curable with respect to the cause. Here,the therapy may only slow the progression of the disease (Jemal et al.2009; CA Cancer J Clin; 59(4): 225-49).

The chemotherapeutics used for the treatment of cancers and also thefrequently used radiation therapy cause strong adverse effects in thepatients (Ladewski et al. 2003; J Clin Oncol. 21(20): 3859-66). This canbe explained by the fact that the action of chemotherapeutics andradiation therapy is not restricted to the cancer cells. There is damageto healthy cells. Especially affected are those cells which exhibitstrong activity with regard to cell division, for example the cells ofthe mucous membranes. For example stomatitis, mucositis, emesis anddiarrhea are observed. Further adverse effects affect the hematopoieticsystem; even nerve cells may be affected.

The strong adverse affects usually associated with a cancer therapystress the patient and are ultimately also a codeterminant as regards towhat extent or in which dose the chemotherapy or radiation therapy canbe used.

There is thus a need for compositions and methods for preventing orweakening the occurrence of adverse effects in cancer therapies. Thiscould improve the tolerance, efficacy and acceptance of the therapy bythe patients. There is also a need for compositions and methods forincreasing the efficacy of chemotherapy or radiation therapy. Increasedefficacy allows the reduction of the doses to be used for the therapyand, as a result, also a reduction of the adverse effects associatedwith the therapy.

DESCRIPTIVE SUMMARY OF THE INVENTION

The invention relates to a composition comprising omega-3 fatty acids.The composition can be used to improve the efficacy of a chemotherapy orof a radiation therapy and/or to prevent or reduce adverse effectscaused by the chemotherapy or the radiation therapy in a patient who hasdeveloped cancer, wherein the composition is to be administered to thepatient prior to the start of a cycle of the chemotherapy or of theradiation therapy.

FIGURES

FIG. 1: Administration regimen for the administration of a compositioncomprising EPA and DHA (Omegaven®) prior to the start of a cycle ofchemotherapy. The figure shows by way of example the consecutiveintravenous administration of Omegaven® two days (“Day 1”) and one day(“Day 2”) prior to the start of a cycle (“Day 3”) of a 5-FU-basedadjuvant chemotherapy in a patient with colorectal cancer. Thechemotherapy regimen applied is known as the FOLFOX regimen. FOLFOX is acombination therapy consisting of the medicaments folinic acid,fluorouracil and oxaliplatin. FOLFOX is the most common therapy regimenfor the treatment of colon cancer. The dose of the medicaments of thechemotherapy is given as mg per m² of body surface area of the patient.Omegaven® is administered in a dose of 2 mL per kg of body weight of thepatient per day. The representation of the days and of the administeredcomposition and medicaments is diagrammatic and the width of the boxesdoes not correspond to the duration of administration.

FIG. 2: Administration regimen for the administration of a compositioncomprising EPA and DHA (Omegaven®) prior to the start of a cycle ofchemotherapy, with the administration also additionally taking place 3hours prior to the start of the cycle. The figure shows by way ofexample the consecutive intravenous administration of Omegaven® two days(“Day 1”), one day (“Day 2”) and on the day of the start (“Day 3”) of acycle of a 5-FU-based adjuvant chemotherapy according to the FOLFOXregimen in a patient with colorectal cancer. The administration on theday of the start of the chemotherapy cycle is carried out 3 hours (“−3h”) prior to the start of the cycle, and is completed no later than onehour (“−1 h”) prior to the start of the cycle. The dose of themedicaments of the chemotherapy is given as mg per m² of body surfacearea of the patient. Omegaven® is administered in a dose of 2 mL per kgof body weight of the patient per day. The representation of the daysand of the administered composition and medicaments is diagrammatic andthe width of the boxes does not correspond to the duration ofadministration.

FIG. 3: Administration regimen for the administration of a compositioncomprising EPA and DHA (Omegaven®) prior to the start of each cycle of achemotherapy comprising 12 cycles. The figure shows by way of examplethe consecutive intravenous administration of Omegaven® two days and oneday prior to each cycle of a 12-cycle-comprising, 5-FU-based adjuvantchemotherapy according to the FOLFOX regimen in a patient withcolorectal cancer. The administration is, in each case, carried outprior to the start of a cycle. One cycle of the chemotherapy encompassestwo days. The cycle is followed by a multiday treatment break in whichthe patient does not receive any chemotherapeutics, and which lastsuntil the start of the next cycle of the chemotherapy. It is followed bythe second cycle of the chemotherapy. Omegaven® is administered prior tothe second cycle, i.e., during the treatment break. The administrationregimen for Omegaven® is carried out in an identical manner for thefollowing cycles 3 to 11 (not shown). Omegaven® is thus administered twodays and one day prior to the start of each cycle of the chemotherapy.However, variations in the administration regimen are also possible inprinciple, provided the administration is carried out prior to the startof the cycle, and provided the administration does not fall into thecycle preceding the particular cycle. The administration prior to thetwelfth (last) cycle of the chemotherapy is carried out as describedabove for cycles 1 to 11. The representation of the days and of theadministered composition and medicaments is diagrammatic and the widthof the boxes does not correspond to the duration of administration.

FIG. 4: Influence of DHA and EPA on the survival of HT-29 cellsfollowing irradiation. The figure shows the survival of HT-29 cellsafter a two-day pretreatment with from 20 μM to 100 μM DHA (A) or EPA(B) followed by irradiation at 0 Gy (white bars), 2 Gy (light-graybars), 4 Gy (medium-gray bars) or 6 Gy (black bars). The values arereported as mean values (%)±standard deviation relative to the untreatedcontrols (6 per group). *P<0.05 compared to 0 Gy; ^(§)P<0.05 compared tountreated control.

DETAILED DESCRIPTION OF THE INVENTION

The invention is defined by the accompanying claims.

Definitions

The term administration encompasses enteral and parenteraladministration.

Enteral administration describes the uptake via the intestine, forexample by oral intake, or by means of transnasal, gastric or jejunalprobes.

In the context of the present invention, parenteral administration isunderstood to mean administration with circumvention of the intestine.It thus encompasses, for example, intravenous injection or infusion andintraarterial injection or infusion. Intraarterial is understood to meanadministration into an arterial blood vessel, and intravenous isunderstood to mean administration into a venous blood vessel. Injectionencompasses administration via a syringe. Generally, it is achieved inthe form of a bolus. However, a continuous injection by means of syringepumps is equally possible. Infusion describes the continuousadministration of the composition into a blood vessel, whichadministration can, for example, be carried out via a peripheral orcentral venous catheter. Transdermal administration (administration viathe skin) is also encompassed.

Chemotherapy is understood to mean the medicamentous therapy of cancerdiseases. A chemotherapy can encompass the treatment with one or moremedicaments, known as chemotherapeutics, for the therapy of cancers. Itis possible to use a combination of medicaments which are administeredat the same time or at different times. Chemotherapeutics used for themedicamentous therapy of cancers are sometimes also used for thetreatment of other diseases, for example severe autoimmune diseases.

FOLFOX is a chemotherapy regimen used for the chemotherapy of colorectalcancer, comprising the medicaments oxaliplatin, folinic acid(leucovorin) and fluorouracil (5-FU).

FOLFIRI is likewise a chemotherapy regimen used for the chemotherapy ofcolorectal cancer, comprising the medicaments folinic acid (leucovorin),fluorouracil (5-FU) and irinotecan.

Radiation therapy encompasses the application of ionizing radiation, forexample gamma radiation, X-radiation and electrons. It also encompassesthe application of neutrons, protons and heavy ions for the treatment ofcancer patients. Radiation therapy can, for example, be carried out inthe form of teletherapy or brachytherapy. In the context of the presentinvention, the expression “administration of irradiation” or“administration of the irradiation” can be used equivalently to theexpression “irradiate”.

In the context of the present invention, a cycle is understood to mean aperiod in which irradiation, a chemotherapeutic, multiplechemotherapeutics or a combination thereof are administered to apatient. In the case of a one-off administration of the irradiation, thechemotherapeutic, multiple chemotherapeutics or a combination thereof,the cycle encompasses the period from the start of the one-offadministration to the end of the one-off administration.

If irradiation, a chemotherapeutic, multiple chemotherapeutics or acombination is administered on successive days, the cycle encompassesthe period from the start of the first administration to the end of thelast administration. The administration of the irradiation, of thechemotherapeutic, of the chemotherapeutics or of a combination thereofcan be carried out at the same time or at different times and can berepeated individually or in combination. If the patient does not receiveirradiation or a chemotherapeutic or multiple chemotherapeutics on a dayfollowing administration of irradiation, of a chemotherapeutic, ofchemotherapeutics or of a combination thereof, the cycle is finishedwith the end of the last administration.

The cycle is followed by a treatment break. This is characterized inthat no irradiation and no chemotherapy are administered to the patientduring the treatment break.

A treatment break can be followed by one or more further cycles. Achemotherapy or radiation therapy can thus comprise one or more cycles.

The start of the first cycle of a chemotherapy or of a radiation therapycan be the time from which a patient receives a particular chemotherapyor a particular radiation therapy for the first time, i.e., the timefrom which irradiation, a chemotherapeutic, multiple chemotherapeuticsor a combination are administered to the patient for the first time. Thestart of a cycle is the time at which the administration of irradiation,of a chemotherapeutic, of multiple chemotherapeutics or a combinationthereof starts. If more than one element selected from the groupconsisting of irradiation, a chemotherapeutic, and multiplechemotherapeutics are administered, the cycle starts with the start ofthe administration of the element which is administered first of all,and ends with the end of the administration of the element which isadministered last.

According to the present invention, solid tumors encompass tumors whichare not derived from the hematopoietic system. Solid tumors are hard,initially localized tumors. The term also encompasses spreading of thetumor to other organs, known as metastases. Solid tumors can be benignor malignant. If a malignant solid tumor appears in a patient, thepatient has developed cancer. All types of solid tumors are encompassed.Preferred solid tumors are colorectal cancer, breast cancer, pancreaticcancer, liver cancer, lung cancer, and stomach cancer. Very particularpreference is given to colorectal cancer.

According to the present invention, the term nonsolid tumors encompassescancer types of the hematopoietic system. The term also encompassesspreading to other organs, known as metastases. The nonsolid tumorsinclude leukemias, comprising acute myeloid leukemia (AML, also referredto as acute nonlymphocytic leukemia (ANLL)), chronic myelogenousleukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocyticleukemia (CLL), and lymphomas, comprising Hodgkin lymphoma andnon-Hodgkin lymphoma.

The term colorectal cancer encompasses cancers of the colon and/or ofthe rectum. Spreading of the colorectal cancer to other organs, known asmetastases, is also encompassed.

In the context of the present invention, improvement in efficacy isunderstood to mean an increase in the efficacy of a chemotherapy orradiation therapy. With improved efficacy, the chemotherapy or radiationtherapy exerts at the same dose a stronger effect on the tumor. This canlead to parameters such as tumor growth, tumor volume, or tumor cellmetastasis, or a combination thereof, being favorably influenced. Animprovement in the efficacy of a chemotherapy or radiation therapy can,for example, lead to an intensified reduction in tumor volume. Animprovement in efficacy can also lead to the tumor volume remainingconstant over a prolonged time, or the tumor growing less rapidly orless strongly than would be the case without the improvement inefficacy. An increase in the efficacy of a chemotherapy or radiationtherapy can result in being able to select a lower dose of the therapyand, nevertheless, being able to achieve the same effect on the tumor asthat provided by the higher dose with no improvement in its efficacy.Increased efficacy can be caused by increased chemosensitivity of thecells.

In medicine, the term chemosensitivity describes the sensitivity ofcancer cells to growth-inhibiting cytostatics. The chemosensitivity ofcancer cells is a frequent codeterminant with regard to the success ofthe chemotherapy.

In the context of the present invention, prevention of adverse effectsis understood to mean prevention of the occurrence of one or moreadverse effects typically associated with a treatment. The reduction ofadverse effects is understood to mean the attenuation of the adverseeffects, i.e., a less strongly pronounced occurrence or a temporallyreduced occurrence of the adverse effect. A person skilled in the art isaware of the adverse effects which may be associated with a treatmentand their manifestations.

Adverse effects are effects which occur in addition to the intendedactual effect of a medicament or of a treatment form. Adverse effectsare also referred to as undesired drug effects.

The adverse effects of chemotherapy for treating cancer patientsinclude, inter alia: gastrointestinal adverse effects (for example, drymouth, inflammation in the mouth, inflammatory changes in the mucousmembrane (mucositis) in the gastrointestinal tract, diarrhea),hematologic adverse effects (for example, anemia, thrombopenia,neutropenia, leukopenia, myelosuppression, disruption of the endogenousimmune system, disruption of blood coagulation), reduction in liverweight, neurotoxic adverse effects (for example, nerve damage,disruption of touch sensitivity or esthesia), adverse effects affectingthe heart such as, for example, cardiac muscle diseases(cardiomyopathy), inflammatory adverse effects, weight loss, limitedfunction of the immune system, hair loss, fatigue, nausea, emesis, or acombination thereof.

The adverse effects observed in the case of radiation therapy include,inter alia: fatigue; loss of appetite, exhaustion, headaches, nausea,emesis, diarrhea, damage to the oral and pharyngeal mucous membrane,damage to the mucous membrane of the digestive tract, damage to thebladder.

Omega-3 fatty acids are polyunsaturated fatty acids in which the lastdouble bond of the fatty acid is in the omega-3 position, i.e., in thethird from last C—C bond seen from the carboxyl end. The omega-3 fattyacids contained in the composition according to the invention can be ofplant or animal origin, for example the fatty acids can be obtained fromalgae or from fish. Preference is given to long-chain and verylong-chain omega-3 fatty acids. Particular preference is given toomega-3 fatty acids selected from the group consisting ofeicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), or acombination thereof.

Long-chain omega-3 fatty acids have a chain length of 12-17 carbonatoms. Very long-chain omega-3 fatty acids (VLCFAs) have a chain lengthof 18-26 carbon atoms. Examples of VLCFAs are linolenic acid,eicosapentaenoic acid and docosahexaenoic acid.

Eicosapentaenoic acid (EPA) or(5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoic acid is apolyunsaturated fatty acid from the class of omega-3 fatty acids havingthe molecular formula C₂₀H₃₀O₂.

Docosahexaenoic acid (DHA) or(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid is apolyunsaturated fatty acid from the class of omega-3 fatty acids havingthe molecular formula C₂₂H₃₂O₂.

Fish oil is understood to mean oil which is obtained from fish and whichcontains omega-3 fatty acids. The fish oil can be obtained from seafishes, for example from deep-sea fishes. Fish oil suitable forparenteral administration in humans is referred to as highly purifiedfish oil.

Medium-chain triglycerides (MCTs) are triglycerides which comprise fattyacid radicals of medium length (a length of from 6 to 12 C atoms).Examples of MCTs are caproic acid (C6), caprylic acid (C8), capric acid(C10), and lauric acid (C12), or a combination thereof.

In the context of the present invention, iron is understood to mean aniron salt suitable for parenteral administration. Moreover,high-molecular-weight iron compounds consisting of a polymeric iron(III)oxide-hydroxide core associated with a carbohydrate shell are alsoencompassed. Examples are iron citrate, iron dextran, iron sulfate,ferric carboxymaltose, iron(II) chloride, iron hydrogen aspartate,iron(II) iodide, iron oxide, iron(III) phosphate, iron(III) sodiumgluconate complex, iron sucrose complex and iron saccharate complex.

Consecutive administration is understood to mean the administration ontwo or more successive days. The consecutive administration can, forexample, be carried out on 2, 3, or 4 successive days. In thisconnection, 24 hours, or else more than or less than 24 hours, can liebetween two successive administrations. It is possible for 0 to 48 hoursto lie between two successive administrations, for example 5 to 42hours, 10 to 38 hours or 12 to 36 hours. For example, the administrationcan be carried out on one day in the morning, but on the following dayat midday or in the evening. It is preferred that 20 to 28 hours,particularly preferably 22 to 26, more preferably 24 hours lie betweentwo successive administrations. For example, the administration canequally be carried out on one day in the evening and on the followingday in the morning or at midday. A consecutive administration on two ormore successive days does not rule out a repeated administration on thesame day. The composition can be administered once, twice, three times,four times or five times per day.

The present invention is based on the finding that an omega-3 fattyacid-comprising composition can be used to improve the efficacy of achemotherapy or of a radiation therapy in a patient who has developedcancer. The composition can equally be used to prevent or reduce adverseeffects caused by the chemotherapy or the radiation therapy in a patientwho has developed cancer.

The composition comprises at least one omega-3 fatty acid. The fattyacids can be EPA, DHA or a combination thereof. The composition cancontain further omega-3 fatty acids. A composition comprising long-chainor very long-chain omega-3 fatty acids is likewise preferred. Thecomposition can comprise one or more different omega-3 fatty acids. If“omega-3 fatty acids” is mentioned in the plural, one or more omega-3fatty acids may be comprised, unless otherwise defined. If “omega-3fatty acids” is mentioned in the singular, one or more omega-3 fattyacids may be comprised, unless otherwise defined.

The composition can comprise further preferred additives, such as MCTs,iron, or a combination thereof.

The composition can be an emulsion.

The composition can be administered enterally or parenterally,preferably parenterally and most preferably intravenously.

The inventors have found out that, surprisingly, the efficacy of thechemotherapy or radiation therapy is improved when a compositioncomprising omega-3 fatty acids such as EPA and DHA is administered priorto the start of a cycle of the therapy. An additional administrationduring the cycle of the therapy or after completion of the cycle islikewise possible. The efficacy of the chemotherapy or radiation therapyis particularly improved when the composition is administeredparenterally. The improvement in efficacy affects cancer cells.

The inventors have also found out that, surprisingly, administration ofthe composition prior to the start of a cycle of the therapy also leadsto the prevention or reduction of adverse effects caused by thechemotherapy or the radiation therapy. A particularly effectiveprevention or reduction of adverse effects caused by the chemotherapy orthe radiation therapy is achieved with parenteral administration of thecomposition according to the invention.

The precise mechanism underlying the invention is unknown. However, itis likely that omega-3 fatty acids can be incorporated more effectivelyinto the cell membranes as a result of the administration thereof priorto the start of a cycle of a chemotherapy or radiation therapy,especially as a result of the parenteral administration thereof, forexample intravenous administration. At the start of the cycle, omega-3fatty acids, preferably EPA and/or DHA, are then already present in thecell membrane of healthy cells, where they can counteract the toxicityof the chemotherapeutics or the irradiation and thus prevent or reducethe adverse effects thereof. Weakening of the effect of thechemotherapeutic or of the radiation therapy on the tumor cell is notobserved. The protective effect of the composition affects the healthycells.

The inventors have found out that, owing to the administration of thecomposition prior to the start of a cycle of a chemotherapy or of aradiation therapy, omega-3 fatty acids such as EPA and/or DHA from thecomposition are advantageously already provided in the body andincorporation into cell membranes has already taken place.

Owing to the parenteral administration, a high dose of omega-3 fattyacids such as EPA and/or DHA can be advantageously administered. Owingto the intravenous administration, the omega-3 fatty acids are providedrapidly for incorporation into the cell membrane; there are no losses inintestinal absorption. The composition according to the inventiontherefore develops especially rapidly its efficacy in terms of theprevention or reduction of adverse effects and the improvement of theefficacy of a chemotherapy or radiation therapy, and even in smallamounts. Even if the composition is only administered just prior to thestart of a cycle of the chemotherapy or of the radiation therapy, forexample if the composition is administered 48 hours or 24 hours prior tothe start of a cycle or even if the composition is administered threehours prior to the start of a cycle, the rapid and direct provisionensures the complete efficacy of the composition. There is no need forprolonged supplementation over several weeks. However, consecutiveadministration on two or more successive days can intensify theincorporation of omega-3 fatty acids, such as DHA and EPA, into the cellmembranes. The composition can, in addition to the administration priorto the start of a cycle, also be administered during and/or after acycle.

Advantageously, in the case of administration of the compositionaccording to the invention, omega-3 fatty acids, such as EPA and DHA,are already present prior to the start of a cycle of a chemotherapy orof a radiation therapy, in contrast to compositions known from the priorart, which have to be administered at the start or after the start of achemotherapy or radiation therapy.

The invention provides a composition which contains omega-3 fatty acids,such as EPA and/or DHA, and is used for use in the improvement of theefficacy of a chemotherapy or of a radiation therapy and/or in theprevention or reduction of adverse effects caused by the chemotherapy orthe radiation therapy in a patient who has developed cancer.

The composition according to the invention is administered to thepatient prior to the start of a cycle of the chemotherapy or of theradiation therapy.

The composition can, in addition to the administration prior to thestart of a cycle, also be effected during the cycle or after the cycle.

The administration can be carried out continuously or intermittently.

The administration can be carried out parenterally. The parenteraladministration is preferably carried out intravenously. The intravenousadministration can be carried out as a continuous infusion or as a bolusadministration.

The composition can be administered such that an intravenousadministration amounts to or does not exceed from 0.05 mL to 5.0 mL perkg of body weight per hour. The intravenous administration can, forexample, amount to or not exceed from 0.1 mL to 5.0 mL, from 0.5 mL to5.0 mL, from 1.0 mL to 5.0 mL, from 1.5 mL to 5.0 mL, from 2.0 mL to 5.0mL, from 2.5 mL to 5.0 mL, from 3.0 mL to 5.0 mL, from 3.5 mL to 5.0 mL,from 4.0 mL to 5.0 mL or from 4.5 mL to 5.0 mL per kg of body weight perhour. The intravenous administration can amount to or not exceed from5.0 mL to 0.05 mL, from 4.5 mL to 0.05 mL, from 4.0 mL to 0.05 mL, from3.5 mL to 0.05 mL, from 3.0 mL to 0.05 mL, from 2.5 mL to 0.05 mL, from2.0 mL to 0.05 mL, from 1.5 mL to 0.05 mL, from 1.0 mL to 0.05 mL orfrom 0.5 mL to 0.05 mL per kg of body weight per hour.

Preferably, the intravenous administration is carried out such that theadministration amounts to or does not exceed from 0.5 mL to 3.5 mL perkg of body weight per hour, preferably from 1.0 mL to 3.0 mL, from 1.5mL to 2.5 mL, most preferably 2.0 mL per kg of body weight per hour.Likewise preferred is an intravenous administration which amounts to ordoes not exceed from 0.3 to 0.5 mL per kg of body weight per hour.

The composition according to the invention can be administered to thepatient prior to the start of the first cycle of the chemotherapy or ofthe radiation therapy. In a preferred embodiment, the compositionaccording to the invention is administered prior to multiple cycles, ineach case prior to the start of a cycle of the chemotherapy or of theradiation therapy. Particular preference is given to administering thecomposition prior to each of the cycles.

The use of the composition according to the invention to improve theefficacy of a chemotherapy or of a radiation therapy and/or to preventor reduce adverse effects caused by the chemotherapy or the radiationtherapy is, in principle, not restricted to particular adverse effects.

The composition according to the invention is used to improve theefficacy of a chemotherapy or of a radiation therapy and/or to preventor reduce adverse effects caused by the chemotherapy or the radiationtherapy, the adverse effects being preferably selected from the groupconsisting of gastrointestinal adverse effects, hematologic adverseeffects, reduction in liver weight, neurotoxic adverse effects, adverseeffects affecting the heart, inflammatory adverse effects, weight loss,limited function of the immune system, reduction of inflammations or acombination thereof.

Very particular preference is given to the use of the compositionaccording to the invention for preventing or reducing adverse effectswhich occur in the case of the chemotherapy or radiation therapy of acolorectal cancer.

The composition according to the invention for use in the improvement ofthe efficacy of a chemotherapy or of a radiation therapy and/or in theprevention or reduction of adverse effects caused by the chemotherapy orthe radiation therapy in a patient who has developed cancer is, inprinciple, not restricted to particular cancers.

In the case of a disease, the composition can be administered to solidor nonsolid tumors.

Preferred solid tumors are selected from the group consisting ofcolorectal cancer, breast cancer, pancreatic cancer, liver cancer, lungcancer, and stomach cancer. Very particular preference is given to thecomposition for use in a patient who has developed colorectal cancer.

The composition according to the invention can be administered in thecase of any form of chemotherapy.

In the chemotherapy, it is possible to use a chemotherapeutic selectedfrom the group consisting of 5-fluorouracil, gemcitabine, doxorubicin,paclitaxel, mitomycin, cyclophosphamide, epirubicin, arabinosylcytosine,tamoxifen, irinotecan, oxaliplatin, folinic acid, cisplatin, taxanes,vinca alkaloids, epipodophyllotoxins, synthetic alkaloids, cytarabine,nitrosourea, dacarbazine, fludarabine, ifosfamide, mitomycin C,tamoxifen or a combination thereof. The chemotherapy can also encompasschemotherapeutics other than and/or further to the aforementioned ones.

More particularly, the composition can also be used when the patientreceives further medicaments and/or enteral or parenteral nutrition inaddition to the chemotherapy or the radiation therapy.

Preferably, the composition according to the invention is administeredfor use in the improvement of the efficacy of a chemotherapy or of aradiation therapy and/or in the prevention or reduction of adverseeffects caused by the chemotherapy or the radiation therapy in the caseof a chemotherapy comprising 5-fluorouracil (5-FU), the chemotherapypreferably being FOLFOX or FOLFIRI.

The radiation therapy can be selected from the group consisting ofteletherapy and brachytherapy.

The composition according to the invention can also be used when thepatient receives chemotherapy and radiation therapy. If the cycle of thechemotherapy and of the radiation therapy does not start at the sametime, the composition according to the invention is preferably to beadministered prior to the one of the two cycles which starts at theearlier time.

The composition according to the invention can comprise from 0.5 g/100mL to 10.0 g/100 mL EPA. The composition can comprise from 1 g/100 mL to10.0 g/100 mL EPA, from 1.5 g/100 mL to 10.0 g/100 mL EPA, from 2 g/100mL to 10.0 g/100 mL EPA, from 2.5 g/100 mL to 10.0 g/100 mL EPA, from 3g/100 mL to 10.0 g/100 mL EPA, from 3.5 g/100 mL to 10.0 g/100 mL EPA,from 4 g/100 mL to 10.0 g/100 mL EPA, from 4.5 g/100 mL to 10.0 g/100 mLEPA, from 5 g/100 mL to 10.0 g/100 mL EPA, from 5.5 g/100 mL to 10.0g/100 mL EPA, from 6 g/100 mL to 10.0 g/100 mL EPA, from 6.5 g/100 mL to10.0 g/100 mL EPA, from 7 g/100 mL to 10.0 g/100 mL EPA, from 7.5 g/100mL to 10.0 g/100 mL EPA, from 8 g/100 mL to 10.0 g/100 mL EPA, from 8.5g/100 mL to 10.0 g/100 mL EPA, from 9 g/100 mL to 10.0 g/100 mL EPA orfrom 9.5 g/100 mL to 10.0 g/100 mL EPA.

The composition can comprise from 0.5 g/100 mL to 9.5 g/100 mL EPA, from0.5 g/100 mL to 9 g/100 mL EPA, from 0.5 g/100 mL to 8.5 g/100 mL EPA,from 0.5 g/100 mL to 8 g/100 mL EPA, from 0.5 g/100 mL to 7.5 g/100 mLEPA, from 0.5 g/100 mL to 7 g/100 mL EPA, from 0.5 g/100 mL to 6.5 g/100mL EPA, from 0.5 g/100 mL to 6 g/100 mL EPA, from 0.5 g/100 mL to 5.5g/100 mL EPA, from 0.5 g/100 mL to 5 g/100 mL EPA, from 0.5 g/100 mL to4.5 g/100 mL EPA, from 0.5 g/100 mL to 4 g/100 mL EPA, from 0.5 g/100 mLto 3.5 g/100 mL EPA, from 0.5 g/100 mL to 3 g/100 mL EPA, from 0.5 g/100mL to 2.5 g/100 mL EPA, from 0.5 g/100 mL to 2 g/100 mL EPA, from 0.5g/100 mL to 1.5 g/100 mL EPA or from 0.5 g/100 mL to 1.0 g/100 mL EPA.

Preferably, the composition comprises from 1.0 g/100 mL to 7.0 g/100 mLEPA. Very particular preference is given to a composition comprisingfrom 1.0 g/100 mL to 4.0 g/100 mL EPA.

The composition can comprise from 0.5 g/100 mL to 10.0 g/100 mL DHA. Thecomposition can comprise from 1 g/100 mL to 10.0 g/100 mL DHA, from 1.5g/100 mL to 10.0 g/100 mL DHA, from 2 g/100 mL to 10.0 g/100 mL DHA,from 2.5 g/100 mL to 10.0 g/100 mL DHA, from 3 g/100 mL to 10.0 g/100 mLDHA, from 3.5 g/100 mL to 10.0 g/100 mL DHA, from 4 g/100 mL to 10.0g/100 mL DHA, from 4.5 g/100 mL to 10.0 g/100 mL DHA, from 5 g/100 mL to10.0 g/100 mL DHA, from 5.5 g/100 mL to 10.0 g/100 mL DHA, from 6 g/100mL to 10.0 g/100 mL DHA, from 6.5 g/100 mL to 10.0 g/100 mL DHA, from 7g/100 mL to 10.0 g/100 mL DHA, from 7.5 g/100 mL to 10.0 g/100 mL DHA,from 8 g/100 mL to 10.0 g/100 mL DHA, from 8.5 g/100 mL to 10.0 g/100 mLDHA, from 9 g/100 mL to 10.0 g/100 mL DHA or from 9.5 g/100 mL to 10.0g/100 mL DHA.

The composition can comprise from 0.5 g/100 mL to 9.5 g/100 mL DHA, from0.5 g/100 mL to 9 g/100 mL DHA, from 0.5 g/100 mL to 8.5 g/100 mL DHA,from 0.5 g/100 mL to 8 g/100 mL DHA, from 0.5 g/100 mL to 7.5 g/100 mLDHA, from 0.5 g/100 mL to 7 g/100 mL DHA, from 0.5 g/100 mL to 6.5 g/100mL DHA, from 0.5 g/100 mL to 6 g/100 mL DHA, from 0.5 g/100 mL to 5.5g/100 mL DHA, from 0.5 g/100 mL to 5 g/100 mL DHA, from 0.5 g/100 mL to4.5 g/100 mL DHA, from 0.5 g/100 mL to 4 g/100 mL DHA, from 0.5 g/100 mLto 3.5 g/100 mL DHA, from 0.5 g/100 mL to 3 g/100 mL DHA, from 0.5 g/100mL to 2.5 g/100 mL DHA, from 0.5 g/100 mL to 2 g/100 mL DHA, from 0.5g/100 mL to 1.5 g/100 mL DHA or from 0.5 g/100 mL to 1.0 g/100 mL DHA.

Preferably, the composition comprises from 1.0 g/100 mL to 7.0 g/100 mLDHA. Very particular preference is given to a composition containingfrom 1.0 g/100 mL to 4.0 g/100 mL DHA.

The composition according to the invention can comprise from 5 g/100 mLto 50 g/100 mL highly purified fish oil. The composition can comprisefrom 10 g/100 mL to 50 g/100 mL highly purified fish oil, from 15 g/100mL to 50 g/100 mL highly purified fish oil, from 20 g/100 mL to 50 g/100mL highly purified fish oil, from 25 g/100 mL to 50 g/100 mL highlypurified fish oil, from 30 g/100 mL to 50 g/100 mL highly purified fishoil, from 35 g/100 mL to 50 g/100 mL highly purified fish oil, from 40g/100 mL to 50 g/100 mL highly purified fish oil, or from 45 g/100 mL to50 g/100 mL highly purified fish oil. The composition can comprise from5 g/100 mL to 45 g/100 mL highly purified fish oil, from 5 g/100 mL to40 g/100 mL highly purified fish oil, from 5 g/100 mL to 35 g/100 mLhighly purified fish oil, from 5 g/100 mL to 30 g/100 mL highly purifiedfish oil, from 5 g/100 mL to 25 g/100 mL highly purified fish oil, from5 g/100 mL to 20 g/100 mL highly purified fish oil, from 5 g/100 mL to15 g/100 mL highly purified fish oil, or from 5 g/100 mL to 10 g/100 mLhighly purified fish oil. Preference is given to a compositioncomprising from 10 g/100 mL to 40 g/100 mL highly purified fish oil, forexample from 15 g/100 mL to 35 g/100 mL highly purified fish oil.

The composition can comprise EPA, DHA or a combination thereof.

Preference is given to the use of Omegaven® (Fresenius Kabi) as thecomposition according to the invention.

Besides omega-3 fatty acids, the composition can also contain furtheradditives. Preferably, the composition according to the inventioncontains further additives selected from medium-chain fatty acids (MCTs)or iron, or a combination thereof. The inventors have found out that,surprisingly, the addition of MCTs and/or iron to the composition leadsto a synergistic effect with the omega-3 fatty acids contained in thecomposition according to the invention, which effect further improvesthe efficacy of the composition.

The composition according to the invention can comprise from 5 g/100 mLto 50 g/100 mL MCTs.

The composition can comprise 10 g/100 mL-50 g/100 mL MCTs, 15 g/100mL-50 g/100 mL MCTs, 20 g/100 mL-50 g/100 mL MCTs, 25 g/100 mL-50 g/100mL MCTs, 30 g/100 mL-50 g/100 mL MCTs, 35 g/100 mL-50 g/100 mL MCTs, 40g/100 mL-50 g/100 mL MCTs, or 45 g/100 mL-50 g/100 mL MCTs. Thecomposition can comprise 5 g/100 mL-45 g/100 mL MCTs, 5 g/100 mL-40g/100 mL MCTs, 5 g/100 mL-35 g/100 mL MCTs, 5 g/100 mL-30 g/100 mL MCTs,5 g/100 mL-25 g/100 mL MCTs, 5 g/100 mL-20 g/100 mL MCTs, 5 g/100 mL-15g/100 mL MCTs, or 5 g/100 mL-10 g/100 mL MCTs. Preference is given to acomposition comprising 10 g/100 mL-40 g/100 mL MCTs, for example 15g/100 mL-35 g/100 mL MCTs.

The composition according to the invention can comprise 0.1 mg/100mL-0.5 mg/100 mL iron. The composition can comprise 0.15 mg/100 mL-0.5mg/100 mL iron, 0.2 mg/100 mL-0.5 mg/100 mL iron, 0.25 mg/100 mL-0.5mg/100 mL iron, 0.3 mg/100 mL-0.5 mg/100 mL iron, 0.35 mg/100 mL-0.5mg/100 mL iron, 0.4 mg/100 mL-0.5 mg/100 mL iron or 0.45 mg/100 mL-0.5mg/100 mL iron. The composition can comprise 0.1 mg/100 mL-0.45 mg/100mL iron, 0.1 mg/100 mL-0.4 mg/100 mL iron, 0.1 mg/100 mL-0.35 mg/100 mLiron, 0.1 mg/100 mL-0.3 mg/100 mL iron, 0.1 mg/100 mL-0.25 mg/100 mLiron, 0.1 mg/100 mL-0.2 mg/100 mL iron, 0.1 mg/100 mL-0.15 mg/100 mLiron. Preference is given to a composition comprising 0.15 mg/100mL-0.45 mg/100 mL iron, for example 0.2 mg/100 mL-0.4 mg/100 mL iron.

The composition is administered prior to the start of a cycle of achemotherapy or radiation therapy. The composition can be administeredfrom 96 hours to 24 hours prior to the start of a cycle, preferably from72 to 24 hours prior to the start of a cycle. Very particular preferenceis given to the composition being administered from 48 to 24 hours priorto the start of a cycle of the chemotherapy or of the radiation therapy.

In addition to the above-described administration prior to the start ofa cycle of a chemotherapy or radiation therapy, the composition can alsoadditionally be administered between 24 hours and 1 hour prior to thestart of the cycle. In this case, administration between 10 and 2 hoursprior to the start of the cycle is advantageous; very particularpreference is given to administration 3 hours prior to the start of acycle.

The composition according to the invention can, in principle, beadministered once or repeatedly prior to the start of a cycle of achemotherapy or radiation therapy. In the case of repeatedadministration, the composition can, for example, be administered twice,three times, four times, or five times. The composition can beadministered consecutively.

Customarily, a chemotherapy or radiation therapy comprises multiplecycles. In this case, the composition can be administered prior to thestart of one cycle or prior to multiple cycles, in each case prior tothe start of the cycle. The composition can be administered prior toeach of the cycles.

The composition can be administered consecutively on multiple successivedays, the composition preferably being administered on three successivedays.

The composition can be administered parenterally, preferablyintravenously.

Using the composition, it is possible to administer from 5 mg to 250 mg,for example from 10 mg to 250 mg, of EPA per kilogram of body weight perday. Preferably, from 25 mg to 250 mg of EPA, from 50 mg to 250 mg ofEPA, from 75 mg to 250 mg of EPA, from 100 mg to 250 mg of EPA, from 125mg to 250 mg of EPA, from 150 mg to 250 mg of EPA, from 175 mg to 250 mgof EPA, from 200 mg to 250 mg of EPA, from 225 mg to 250 mg of EPA perkilogram of body weight per day may be administered. It is possible toadminister from 5 mg to 10 mg of EPA, from 5 mg to 25 mg of EPA, from 5mg to 50 mg of EPA, from 5 mg to 75 mg of EPA, from 5 mg to 100 mg ofEPA, from 5 mg to 125 mg of EPA, from 5 mg to 150 mg of EPA, from 5 mgto 175 mg of EPA, from 5 mg to 200 mg of EPA or from 5 mg to 225 mg ofEPA per kilogram of body weight per day.

Using the composition, preference is given to administering from 5 mg to100 mg of EPA, for example from 15 mg to 85 mg of EPA, from 20 mg to 80mg of EPA, from 25 mg to 75 mg of EPA, from 30 mg to 70 mg of EPA, from35 mg to 65 mg of EPA, or from 40 mg to 60 mg of EPA, per kilogram ofbody weight per day. Very particular preference is given toadministration of from 45 mg to 55 mg of EPA, 45 mg of EPA, 46 mg ofEPA, 47 mg of EPA, 48 mg of EPA, 49 mg of EPA, 50 mg of EPA, 51 mg ofEPA, 52 mg of EPA, 53 mg of EPA, 54 mg of EPA, or 55 mg of EPA perkilogram of body weight per day.

Using the composition, it is possible to administer from 5 mg to 250 mg,for example from 10 mg to 250 mg, of DHA per kilogram of body weight perday. Preferably, from 25 mg to 250 mg of DHA, from 50 mg to 250 mg ofDHA, from 75 mg to 250 mg of DHA, from 100 mg to 250 mg of DHA, from 125mg to 250 mg of DHA, from 150 mg to 250 mg of DHA, from 175 mg to 250 mgof DHA, from 200 mg to 250 mg of DHA, from 225 mg to 250 mg of DHA perkilogram of body weight per day may be administered. It is possible toadminister from 5 mg to 10 mg of DHA, from 5 mg to 25 mg of DHA, from 5mg to 50 mg of DHA, from 5 mg to 75 mg of DHA, from 5 mg to 100 mg ofDHA, from 5 mg to 125 mg of DHA, from 5 mg to 150 mg of DHA, from 5 mgto 175 mg of DHA, from 5 mg to 200 mg of DHA or from 5 mg to 225 mg ofDHA per kilogram of body weight per day.

Using the composition, preference is given to administering from 5 mg to100 mg of DHA, for example from 15 mg to 85 mg of DHA, from 20 mg to 80mg of DHA, from 25 mg to 75 mg of DHA, from 30 mg to 70 mg of DHA, from35 mg to 65 mg of DHA, or from 40 mg to 60 mg of DHA, per kilogram ofbody weight per day. Very particular preference is given toadministration of from 45 mg to 55 mg of DHA, 45 mg of DHA, 46 mg ofDHA, 47 mg of DHA, 48 mg of DHA, 49 mg of DHA, 50 mg of DHA, 51 mg ofDHA, 52 mg of DHA, 53 mg of DHA, 54 mg of DHA, or 55 mg of DHA perkilogram of body weight per day.

Using the composition, it is possible to administer from 0.025 g to 1.25g of fish oil per kilogram of body weight per day. For example, it ispossible to administer from 0.05 g to 1.25 g of fish oil, from 0.075 gto 1.25 g of fish oil, from 0.1 g to 1.25 g of fish oil, from 0.2 g to1.25 g of fish oil, from 0.3 g to 1.25 g of fish oil, from 0.4 g to 1.25g of fish oil, from 0.5 g to 1.25 g of fish oil, from 0.6 g to 1.25 g offish oil, from 0.7 g to 1.25 g of fish oil, from 0.8 g to 1.25 g of fishoil, from 0.9 g to 1.25 g of fish oil or from 1.0 g to 1.25 g of fishoil per kilogram of body weight per day. It is possible to administerfrom 1.0 g to 0.025 g of fish oil, from 1.0 g to 0.025 g of fish oil,from 0.9 g to 0.025 g of fish oil, from 0.8 g to 0.025 g of fish oil,from 0.7 g to 0.025 g of fish oil, from 0.6 g to 0.025 g of fish oil,from 0.5 g to 0.025 g of fish oil, from 0.4 g to 0.025 g of fish oil,from 0.3 g to 0.025 g of fish oil, from 0.3 g to 0.025 g of fish oil,from 0.2 g to 0.025 g of fish oil, from 0.1 g to 0.025 g of fish oil,from 0.075 g to 0.025 g of fish oil or from 0.05 g to 0.025 g of fishoil per kilogram of body weight per day.

Preference is given to the administration of from 0.1 g to 0.7 g of fishoil, from 0.15 g to 0.65 g of fish oil, from 0.2 g to 0.6 g of fish oil,from 0.25 g to 0.55 g of fish oil per kilogram of body weight per day.Very particular preference is given to the administration of from 0.3 gto 0.5 g of fish oil per kilogram of body weight per day. And likewisepreferred is the administration of 0.2 g of fish oil per kilogram ofbody weight per day. The fish oil can be highly purified.

Most preference is given to the use of Omegaven® (Fresenius Kabi) as thecomposition according to the invention. Omegaven® can be administered ina dose of from 0.25 mL to 12.5 mL per kg of body weight per day. Forexample, it is possible to administer from 0.5 mL to 12.5 mL, from 1.0mL to 12.5 mL, from 1.5 mL to 12.5 mL, from 2.0 mL to 12.5 mL, from 2.5mL to 12.5 mL, from 3.0 mL to 12.5 mL, from 3.5 mL to 12.5 mL, from 4.0mL to 12.5 mL, from 4.5 mL to 12.5 mL, from 5.0 mL to 12.5 mL, from 5.5mL to 12.5 mL, from 6.0 mL to 12.5 mL, from 7.0 mL to 12.5 mL, from 8.0mL to 12.5 mL, from 9.0 mL to 12.5 mL, from 10.0 mL to 12.5 mL, from11.0 mL to 12.5 mL, from 11.5 mL to 12.5 mL or from 12.0 mL to 12.5 mLof Omegaven® per kg of body weight per day. It is possible to administerfrom 12.0 mL to 0.25 mL, from 11.5 mL to 0.25 mL, from 11.0 mL to 0.25mL, from 10.0 mL to 0.25 mL, from 9.0 mL to 0.25 mL, from 8.0 mL to 0.25mL, from 7.0 mL to 0.25 mL, from 6.0 mL to 0.25 mL, from 5.5 mL to 0.25mL, from 4.0 mL to 0.25 mL, from 3.5 mL to 0.25 mL, from 3.0 mL to 0.25mL, from 2.5 mL to 0.25 mL, from 2.0 mL to 0.25 mL, from 1.5 mL to 0.25mL, from 1.0 mL to 0.25 mL, from 0.75 mL to 0.25 mL, or from 0.5 mL to0.25 mL of Omegaven® per kilogram of body weight per day.

Preference is given to administration of from 1.0 mL to 7.0 mL, from 1.5mL to 6.5 mL, from 2.0 mL to 6.0 mL or from 2.5 mL to 5.5 mL ofOmegaven® per kilogram of body weight per day. Very particularpreference is given to administration of from 3.0 mL to 5.0 mL ofOmegaven® per kilogram of body weight per day. Likewise preferred is theadministration of 2.0 mL of Omegaven® per kilogram of body weight perday.

Using the composition, it is possible to administer from 0.07 g to 0.7 gof MCTs per kilogram of body weight per day. It is possible toadminister from 0.1 g to 0.7 g of MCTs, from 0.2 g to 0.7 g of MCTs,from 0.25 g to 0.7 g of MCTs, from 0.3 g to 0.7 g of MCTs, from 0.35 gto 0.7 g of MCTs, from 0.4 g to 0.7 g of MCTs, from 0.45 g to 0.7 g ofMCTs, from 0.5 g to 0.7 g of MCTs, from 0.55 g to 0.7 g of MCTs, from0.6 g to 0.7 g of MCTs or from 0.65 g to 0.7 g of MCTs per kilogram ofbody weight per day. Using the composition, it is possible to administerfrom 0.65 g to 0.07 g of MCTs, from 0.6 g to 0.07 g of MCTs, from 0.55 gto 0.07 g of MCTs, from 0.5 g to 0.07 g of MCTs, from 0.45 g to 0.07 gof MCTs, from 0.4 g to 0.07 g of MCTs, from 0.35 g to 0.07 g of MCTs,from 0.3 g to 0.07 g of MCTs, from 0.25 g to 0.07 g of MCTs, from 0.2 gto 0.07 g of MCTs, from 0.15 g to 0.07 g of MCTs or from 0.1 g to 0.07 gof MCTs per kilogram of body weight per day.

Preference is given to the administration of from 0.1 g to 0.5 g ofMCTs, from 0.2 g to 0.6 g of MCTs, from 0.3 g to 0.5 g of MCTs or from0.35 g to 0.45 g of MCTs per kilogram of body weight per day.

Using the composition, it is possible to administer from 1 mg to 11 mgof iron per day. It is possible to administer 1 mg-10 mg of iron, 1 mg-9mg of iron, 1 mg-8 mg of iron, 1 mg-7 mg of iron, 1 mg-6 mg of iron, 1mg-5 mg of iron, 1 mg-4 mg of iron, 1 mg-3 mg of iron, 1 mg-2 mg of ironper day. It is possible to administer 2 mg-11 mg of iron, 3 mg-11 mg ofiron, 4 mg-11 mg of iron, 5 mg-11 mg of iron, 6 mg-11 mg of iron, 7mg-11 mg of iron, 8 mg-11 mg of iron, 9 mg-11 mg of iron, or 10 mg-11 mgof iron per day. Preference is given to administration of 3 mg-9 mg ofiron per day.

A composition having a volume of 100 mL and comprising omega-3 fattyacids is provided. The composition can comprise one or more differentomega-3 fatty acids. Preferably, the composition comprises omega-3 fattyacids selected from the group consisting of EPA, DHA, long-chain andvery long-chain omega-3 fatty acids or a combination thereof. Particularpreference is given to a composition having a volume of 100 mL andcomprising from 0.5 g to 10 g of EPA and/or from 0.5 g to 10 g of DHA.The composition can comprise fish oil, for example from 5 g/100 mL to 50g/100 mL. The provided composition can further comprise MCTs and/oriron. The composition can comprise from 5 g/100 mL to 50 g/100 mL MCTsand/or 0.1 mg/100 mL-0.5 mg/100 mL iron.

The provided composition according to the invention having a volume of100 mL can comprise from 0.5 g to 10.0 g of EPA. The composition cancomprise from 1 g to 10.0 g of EPA, from 1.5 g to 10.0 g of EPA, from 2g to 10.0 g of EPA, from 2.5 g to 10.0 g of EPA, from 3 g to 10.0 g ofEPA, from 3.5 g to 10.0 g of EPA, from 4 g to 10.0 g of EPA, from 4.5 gto 10.0 g of EPA, from 5 g to 10.0 g of EPA, from 5.5 g to 10.0 g ofEPA, from 6 g to 10.0 g of EPA, from 6.5 g to 10.0 g of EPA, from 7 g to10.0 g of EPA, from 7.5 g to 10.0 g of EPA, from 8 g to 10.0 g of EPA,from 8.5 g to 10.0 g of EPA, from 9 g to 10.0 g of EPA or from 9.5 g to10.0 g of EPA.

The composition can comprise from 0.5 g to 9.5 g of EPA, from 0.5 g to 9g of EPA, from 0.5 g to 8.5 g of EPA, from 0.5 g to 8 g of EPA, from 0.5g to 7.5 g of EPA, from 0.5 g to 7 g of EPA, from 0.5 g to 6.5 g of EPA,from 0.5 g to 6 g of EPA, from 0.5 g to 5.5 g of EPA, from 0.5 g to 5 gof EPA, from 0.5 g to 4.5 g of EPA, from 0.5 g to 4 g of EPA, from 0.5 gto 3.5 g of EPA, from 0.5 g to 3 g of EPA, from 0.5 g to 2.5 g of EPA,from 0.5 g to 2 g of EPA, from 0.5 g to 1.5 g of EPA or from 0.5 g to1.0 g of EPA.

Preferably, the composition comprises from 1.0 g to 7.0 g of EPA. Veryparticular preference is given to a composition comprising from 1.0 g to4.0 g of EPA.

The provided composition according to the invention having a volume of100 mL can comprise from 0.5 g to 10.0 g of DHA. The composition cancomprise from 1 g to 10.0 g of DHA, from 1.5 g to 10.0 g of DHA, from 2g to 10.0 g of DHA, from 2.5 g to 10.0 g of DHA, from 3 g to 10.0 g ofDHA, from 3.5 g to 10.0 g of DHA, from 4 g to 10.0 g of DHA, from 4.5 gto 10.0 g of DHA, from 5 g to 10.0 g of DHA, from 5.5 g to 10.0 g ofDHA, from 6 g to 10.0 g of DHA, from 6.5 g to 10.0 g of DHA, from 7 g to10.0 g of DHA, from 7.5 g to 10.0 g of DHA, from 8 g to 10.0 g of DHA,from 8.5 g to 10.0 g of DHA, from 9 g to 10.0 g of DHA or from 9.5 g to10.0 g of DHA.

The provided composition according to the invention having a volume of100 mL can comprise from 0.5 g to 9.5 g of DHA, from 0.5 g to 9 g ofDHA, from 0.5 g to 8.5 g of DHA, from 0.5 g to 8 g of DHA, from 0.5 g to7.5 g of DHA, from 0.5 g to 7 g of DHA, from 0.5 g to 6.5 g of DHA, from0.5 g to 6 g of DHA, from 0.5 g to 5.5 g of DHA, from 0.5 g to 5 g ofDHA, from 0.5 g to 4.5 g of DHA, from 0.5 g to 4 g of DHA, from 0.5 g to3.5 g of DHA, from 0.5 g to 3 g of DHA, from 0.5 g to 2.5 g of DHA, from0.5 g to 2 g of DHA, from 0.5 g to 1.5 g of DHA or from 0.5 g to 1.0 gof DHA.

Preferably, the composition comprises from 1.0 g to 7.0 g of DHA. Veryparticular preference is given to a composition comprising from 1.0 g to4.0 g of DHA.

The provided composition according to the invention having a volume of100 mL can comprise 5 g-50 g of highly purified fish oil. Thecomposition can comprise 10 g-50 g of highly purified fish oil, 15 g-50g of highly purified fish oil, 20 g-50 g of highly purified fish oil, 25g-50 g of highly purified fish oil, 30 g-50 g of highly purified fishoil, 35 g-50 g of highly purified fish oil, 40 g-50 g of highly purifiedfish oil, or 45 g-50 g of highly purified fish oil. The composition cancomprise 5 g-45 g of highly purified fish oil, 5 g-40 g of highlypurified fish oil, 5 g-35 g of highly purified fish oil, 5 g-30 g ofhighly purified fish oil, 5 g-25 g of highly purified fish oil, 5 g-20 gof highly purified fish oil, 5 g-15 g of highly purified fish oil, or 5g-10 g of highly purified fish oil. Preference is given to a compositioncomprising 10 g-40 g of highly purified fish oil, for example 15 g-35 gof highly purified fish oil.

The composition can comprise EPA, DHA or a combination thereof.

The provided composition according to the invention having a volume of100 mL can comprise from 5 g to 50 g of MCTs. The composition cancomprise from 10 g to 50 g of MCTs, from 15 g to 50 g of MCTs, from 20 gto 50 g of MCTs, from 25 g to 50 g of MCTs, from 30 g to 50 g of MCTs,from 35 g to 50 g of MCTs, from 40 g to 50 g of MCTs, or from 45 g to 50g of MCTs. The composition can comprise from 5 g to 10 g of MCTs, from 5g to 15 g of MCTs, from 5 g to 20 g of MCTs, from 5 g to 25 g of MCTs,from 5 g to 30 g of MCTs, from 5 g to 35 g of MCTs, from 5 g to 40 g ofMCTs, or from 5 g to 45 g of MCTs. Preference is given to a compositioncomprising from 10 g to 40 g of MCTs, for example from 15 g to 35 g.

The provided composition according to the invention having a volume of100 mL can comprise 0.1 mg-0.5 mg of iron. The composition can comprise0.15 mg-0.5 mg of iron, 0.2 mg-0.5 mg of iron, 0.25 mg-0.5 mg of iron,0.3 mg-0.5 mg of iron, 0.35 mg-0.5 mg of iron, 0.4 mg-0.5 mg of iron or0.45 mg-0.5 mg of iron. The composition can comprise 0.1 mg-0.45 mg ofiron, 0.1 mg-0.4 mg of iron, 0.1 mg-0.35 mg of iron, 0.1 mg-0.3 mg ofiron, 0.1 mg-0.25 mg of iron, 0.1 mg-0.2 mg of iron, 0.1 mg-0.15 mg ofiron. Preference is given to a composition comprising 0.15 mg-0.45 mg ofiron, for example 0.2 mg-0.4 mg of iron.

A composition having a volume of 50 mL is disclosed, which differs fromthe above-disclosed solution having a volume of 100 mL in that itcomprises only half the amount of each ingredient disclosed for thecomposition having the volume of 100 mL.

A method for administering the composition according to the invention isprovided.

There is provided a method for administering a composition comprisingomega-3 fatty acids selected from eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), or a combination thereof, to a patient whohas developed cancer, in order to improve the efficacy of a chemotherapyor of a radiation therapy and/or to prevent or reduce adverse effectscaused by the chemotherapy or the radiation therapy, the methodcomprising the following steps: (a) the administration of thecomposition to the patient prior to the start of a cycle of thechemotherapy or of the radiation therapy; (b) treatment of the patientwith at least one cycle of a chemotherapy or radiation therapy.

There is provided the method for administering a composition comprisingomega-3 fatty acids selected from eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), or a combination thereof, to a patient whohas developed cancer, in order to improve the efficacy of a chemotherapyor of a radiation therapy and/or to prevent or reduce adverse effectscaused by the chemotherapy or the radiation therapy, the methodcomprising the following steps: (a) the administration of thecomposition prior to the start of a cycle of the chemotherapy or of theradiation therapy, wherein the composition is administered from 96 hoursto 24 hours prior to the start of a cycle of the chemotherapy or of theradiation therapy, preferably wherein the composition is administeredfrom 72 to 24 hours prior to the start of a cycle of the chemotherapy orof the radiation therapy, very particularly preferably wherein thecomposition is administered from 48 to 24 hours prior to the start of acycle of the chemotherapy or of the radiation therapy; (b) treatment ofthe patient with at least one cycle of a chemotherapy or radiationtherapy.

The administration in step (a) can be carried out once or repeatedly,for example twice, three times, four times or five times. In step (b),the patient can be treated with, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, or 15 cycles of a chemotherapy or radiation therapy.

The method can further comprise the step: (a)′ additional administrationof the composition is also additionally administered between 24 hoursand 1 hour prior to the start of the cycle of the chemotherapy orradiation therapy, preferably wherein the composition is administered 3hours prior to the start of a cycle of the chemotherapy or of theradiation therapy. The administration in step (a)′ can be carried outonce or repeatedly, for example twice, three times, four times or fivetimes.

The method can be carried out such that from 5 mg to 250 mg of EPA perkilogram of body weight per day are administered, preferably whereinfrom 20 mg to 80 mg of EPA per kilogram of body weight per day areadministered, most preferably wherein from 40 mg to 60 mg of EPA perkilogram of body weight per day are administered, and/or such that from5 mg to 250 mg of DHA per kilogram of body weight per day areadministered, preferably wherein from 20 mg to 80 mg of DHA per kilogramof body weight per day are administered, most preferably wherein from 40mg to 60 mg of DHA per kilogram of body weight per day are administered.

Steps (a) and/or (a)′ of the method can be repeated, wherein thecomposition is preferably administered consecutively on multiplesuccessive days, preferably wherein the composition is administered onthree successive days.

The composition can be administered parenterally, preferablyintravenously.

The method can additionally comprise the step: (c) additionaladministration of the composition during or after a cycle of thechemotherapy or radiation therapy. The method can be used to prevent orreduce adverse effects caused by the chemotherapy or the radiationtherapy, wherein the adverse effects are preferably selected from thegroup consisting of gastrointestinal adverse effects, hematologicadverse effects, reduction in liver weight, neurotoxic adverse effects,adverse effects affecting the heart, inflammatory adverse effects,weight loss, limited function of the immune system, reduction ofinflammations or a combination thereof.

The method can be used to treat cancers, wherein the cancer is selectedfrom the group consisting of solid tumors and nonsolid tumors,preferably wherein the solid tumors are selected from the groupconsisting of colorectal cancer, breast cancer, pancreatic cancer, livercancer, lung cancer, and stomach cancer.

The method can be used in patients receiving chemotherapy, preferablywherein the chemotherapy comprises a chemotherapeutic selected from thegroup consisting of 5-fluorouracil, gemcitabine, doxorubicin,paclitaxel, mitomycin, cyclophosphamide, epirubicin, arabinosylcytosine,tamoxifen, irinotecan, oxaliplatin, folinic acid, cisplatin, taxanes,vinca alkaloids, epipodophyllotoxins, synthetic alkaloids, cytarabine,nitrosourea, dacarbazine, fludarabine, ifosfamide, mitomycin C,tamoxifen or a combination thereof.

Particular preference is given to the method in which the chemotherapycomprises 5-fluorouracil, and very particular preference is given to themethod in which the chemotherapy is FOLFOX or FOLFIRI.

The method can be used in patients receiving radiation therapy,preferably wherein the radiation therapy is selected from the groupconsisting of teletherapy and brachytherapy.

The composition administered by means of the method can contain furtherpreferred additives selected from the group consisting of medium-chainfatty acids and iron, or a combination thereof.

The composition administered by means of the method can contain from 0.5g/100 mL to 10.0 g/100 mL EPA and/or from 0.5 g/100 mL to 10.0 g/100 mLDHA, preferably from 0.7 g/100 mL to 3.5 g/100 mL EPA and/or from 0.7g/100 mL to 3.5 g/100 mL DHA. Very particular preference is given to thecomposition containing from 1 g/100 mL to 3.1 g/100 mL EPA and/or DHA.

The abovementioned values and ranges are individually comprehended andcomprehended in combination. Each value of a range is individuallycomprehended, more particularly all integral intermediate values.

EXAMPLES Example 1 Preparation of Composition ComprisingEicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA)

a) A composition comprising the following constituents (values based on100 mL, unless otherwise indicated) was prepared:

Eicosapentaenoic acid (EPA) 0.5 g-5 g or 2.5 gb) A composition comprising the following constituents (values based on100 mL, unless otherwise indicated) was prepared:

Docosahexaenoic acid (DHA) 0.5 g-5 g or 2.5 gc) A composition comprising the following constituents (values based on100 mL, unless otherwise indicated) was prepared:

Eicosapentaenoic acid (EPA) 0.5 g-5 g or 2.5 g Docosahexaenoic acid(DHA) 0.5 g-5 g or 2.5 gd) A composition comprising the following constituents (values based on100 mL, unless otherwise indicated) was prepared:

Highly purified fish oil 5 g-50 g or 25 g

Sodium oleate, sodium hydroxide, and water for injection are used asexcipients.

Example 2 Preparation of Composition Comprising Eicosapentaenoic Acid(EPA) and/or Docosahexaenoic Acid (DHA) with Admixtures (MCTs, Iron)

a) A composition comprising the following constituents (values based on100 mL, unless otherwise indicated) was prepared:

Eicosapentaenoic acid (EPA) 0.5 g-5 g or 2.5 g MCTs 5 g-50 g or 25 gb) A composition comprising the following constituents (values based on100 mL, unless otherwise indicated) was prepared:

Docosahexaenoic acid (DHA) 0.5 g-5 g or 2.5 g MCTs 5 g-50 g or 25 gc) A composition comprising the following constituents (values based on100 mL, unless otherwise indicated) was prepared:

Eicosapentaenoic acid (EPA) 0.5 g-5 g or 2.5 g Docosahexaenoic acid(DHA) 0.5 g-5 g or 2.5 g MCTs 5 g-50 g or 25 gd) A composition comprising the following constituents (values based on100 mL, unless otherwise indicated) was prepared:

Eicosapentaenoic acid (EPA) 0.5 g-5 g or 2.5 g Iron 0.1 mg-5 mg or 2.5mge) A composition comprising the following constituents (values based on100 mL, unless otherwise indicated) was prepared:

Docosahexaenoic acid (DHA) 0.5 g-5 g or 2.5 g Iron 0.1 mg-5 mg or 2.5 mgf) A composition comprising the following constituents (values based on100 mL, unless otherwise indicated) was prepared:

Eicosapentaenoic acid (EPA) 0.5 g-5 g or 2.5 g Docosahexaenoic acid(DHA) 0.5 g-5 g or 2.5 g Iron 0.1 mg-5 mg or 2.5 mgg) A composition comprising the following constituents (values based on100 mL, unless otherwise indicated) was prepared:

Eicosapentaenoic acid (EPA) 0.5 g-5 g or 2.5 g MCTs 5 g-50 g or 25 gIron 0.1 mg-5 mg or 2.5 mgh) A composition comprising the following constituents (values based on100 mL, unless otherwise indicated) was prepared:

Docosahexaenoic acid (DHA) 0.5 g-5 g or 2.5 g MCTs 5 g-50 g or 25 g Iron0.1 mg-5 mg or 2.5 mgi) A composition comprising the following constituents (values based on100 mL, unless otherwise indicated) was prepared:

Eicosapentaenoic acid (EPA) 0.5 g-5 g or 2.5 g Docosahexaenoic acid(DHA) 0.5 g-5 g or 2.5 g MCTs 5 g-50 g or 25 g Iron 0.1 mg-5 mg or 2.5mgj) A composition comprising the following constituents (values based on100 mL, unless otherwise indicated) was prepared:

Highly purified fish oil 5g-50 g or 25 g MCTs 5 g-50 g or 25 gk) A composition comprising the following constituents (values based on100 mL, unless otherwise indicated) was prepared:

Highly purified fish oil 5 g-50 g or 25 g Iron 0.1 mg-5 mg or 2.5 mgl) A composition comprising the following constituents (values based on100 mL, unless otherwise indicated) was prepared:

Highly purified fish oil 5 g-50 g or 25 g MCTs 5 g-50 g or 25 g Iron 0.1mg-5 mg or 2.5 mg

Example 3 Preparation of Omegaven®

An emulsion (Omegaven®) comprising the following constituents (valuesbased on 100 mL, unless otherwise indicated) was prepared:

Highly purified fish oil containing: 10.0 g eicosapentaenoic acid (EPA)1.25 g-2.82 g docosahexaenoic acid (DHA) 1.44 g-3.09 g myristic acid 0.1g-0.6 g palmitic acid 0.25 g-1.0 g  palmitoleic acid 0.3 g-0.9 g stearicacid 0.05 g-0.2 g  oleic acid 0.6 g-1.3 g linoleic acid 0.1 g-0.7 glinolenic acid ≦0.2 g octadecatetraenoic acid 0.05 g-0.65 g eicosaenoicacid 0.05 g-0.3 g  arachidonic acid 0.1 g-0.4 g docosaenoic acid ≦0.15 gdocosapentaenoic acid 0.15 g-0.45 g dl-α-tocopherol  0.015 g-0.0296 gGlycerol 2.5 g Purified phosphatides from egg 1.2 g Total energy 470kJ/100 mL; 112 kcal/100 mL pH 7.5-8.5 Titration acid <1 mmol HCl/LOsmolarity 308-367 mosm/kg

Sodium oleate, sodium hydroxide and water for injection are used asexcipients.

Example 4 Intravenous Administration of a Composition Comprising EPA andDHA

Consecutive intravenous administration of Omegaven® was carried out twodays and one day prior to the start of a cycle of a 5-FU-based adjuvantchemotherapy in a patient with colorectal cancer. The chemotherapyregimen applied for the patient is the so-called FOLFOX regimen.Omegaven® is administered in a dose of 2 mL per kg of patient bodyweight per day (see also FIGS. 1 and 3).

The intravenous administration of Omegaven® is, in each case, carriedout prior to the start of a cycle of a chemotherapy comprising 12cycles. Omegaven® is administered prior to each of the 12 cycles. Eachcycle is followed by a multiday treatment break in which the patientdoes not receive any chemotherapeutics, and which lasts until the startof the next cycle of the chemotherapy. Omegaven® is, in each case,administered prior to the start of a cycle, i.e., during the treatmentbreak.

Consecutive intravenous administration of Omegaven® is carried out twodays, one day and on the day of the start of a cycle of a 5-FU-basedadjuvant chemotherapy according to the FOLFOX regimen in a patient withcolorectal cancer. The administration on the day of the start of thechemotherapy cycle is carried out 3 hours prior to the start of thecycle, and is completed no later than one hour prior to the start of thecycle. Omegaven® is administered in a dose of 2 mL per kg of patientbody weight per day (see also FIG. 2).

Example 5 Investigation of the Influence of a Composition Comprising EPAand DHA on the Efficacy of the Chemotherapy and on Chemotherapy-InducedAdverse Effects in a Mouse Model of Human Colorectal Cancer

The experiment uses female NMRI nu/nu mice (Elevage Janvier, Le GenestSt Isle, France) aged between 7 and 8 weeks and weighing about 25 g.After receipt, the animals are injected with 2×10⁶ cells/0.1 mL of thehuman colorectal-cancer cell line LS174T, and kept in isolator cages fortwo weeks under standardized, defined pathogen-free conditions;autoclaved litter and feed are used.

Two weeks after the inoculation with tumor cells, mice having tumors ofabout 30 mm³ are divided up into the various experimental groups. Thedivision is carried out such that comparable mean tumor volumes arepresent among the groups.

Animals of group A receive, 48 hours and 24 hours prior to the start ofa treatment with 5-FU, an intravenous infusion with Omegaven® in eachcase (2 mL per kg of body weight per day; corresponding to 60 μL ofOmegaven® per 200 μL of saline in the case of a weight of 30 g). Theinjection is carried out via the tail vein. Animals of group B receive,in addition to the infusion with Omegaven® 48 hours and 24 hours, afurther infusion with Omegaven® three hours prior to the start of thetreatment with 5-FU. Animals of control group C receive, 48 hours and 24hours prior to the start of the treatment with 5-FU, an intravenousinfusion with Lipovenös® in each case in an appropriate dose. Animals ofcontrol group D receive, 24 hours and 48 hours after the start of thetreatment with 5-FU, an intravenous infusion with Omegaven® in each case(2 mL per kg of body weight per day). The treatment with 5-FU (50 mg perkg of body weight per day) is carried out by intraperitoneal injectionon seven successive days.

Influence on the Efficacy of the Chemotherapy

Tumor growth is determined by the measurement of the three orthogonaltumor diameters using a caliper by means of the formula

Tumor volume=4π/3×(length/2×width/2×height/2)

The measurement is carried out every two days. Changes in tumor volumeare calculated with reference to the initial tumor volume of an animal.

It is shown that animals of groups A and B have a lower mean tumorvolume compared to animals of groups C and D. A trend toward a reducedtumor volume in the animals of group B compared to group A is observed.

In addition, in some of the animals at the end of the experiment, theincorporation of [¹²⁵I] in various tissues is determined byinvestigating the distribution of the radioactivity after a two-daypretreatment with potassium iodide and perchlorate in drinking water (toinhibit the uptake of radioactive iodine into thymus and stomach) and aone-off intravenous injection with 250 KBq of [¹²⁵I]. 24 hours after theinjection, the animals are killed by CO₂ inhalation and theradioactivity in the tumor and in the various organs (lungs, heart,liver, stomach, small intestine, large intestine, spleen, kidneys) ismeasured in a y counter (Cobra QC 5002, Packard, US). The organ weightsare recorded.

On the basis of the comparison of the observed mean incorporation of[¹²⁵I] in the tumors of the animals of the various groups, it becomesapparent that administration of Omegaven prior to the start of thechemotherapy (groups A, B) is advantageous.

Influence on the Adverse Effects of the Chemotherapy:

To investigate the influence of an EPA- and DHA-containing composition(Omegaven®) on the adverse effects occurring in the case of thechemotherapy with 5-FU, various parameters are recorded from some of theanimals treated as described above, at the end of the treatment with5-FU, and these include liver weight, PEG₂ activity in liver homogenates(Bicyclo-PEG2 Enzyme Immunoassay Kit; Cayman Chemical, Ann Arbor, Mich.,USA), and the extent of changes in the intestinal tract of the animals(examination of crypt height and apoptotic figures in formalin-fixed,paraffin-embedded histological preparations following hemalaun and eosinstaining), and changes in the blood count (determination of the cellcounts of the individual cellular blood components on the Cell-Dyn3500R).

The liver weight of the animals of groups A and B is higher than that ofthe animals of group C, and the animals have a lower relative content ofPGE₂. In comparison to control group C, fewer changes in crypt and cellstructure of the normal mucous membrane of the intestine occur inanimals of groups A and B. In comparison to animals of control group C,the animals of groups A and B have a more favorable blood count which iscloser to normal values.

Example 6 Investigation of the Influence of EPA and DHA on theIrradiation Sensitivity of Human Colorectal Cells In Vitro

HT-29 colorectal cancer cells (ATCC number HTB-38) were cultured inDulbecco's Modified Eagle's Medium (DMEM, product number D 5030, SigmaChemie AG, Buchs, Switzerland) supplemented with 10% heat-inactivatedfetal calf serum (FBS), 1 g/L D-glucose, 3.7 g/L sodium bicarbonate and0.1 g/L penicillin-streptomycin (all additives from Life TechnologiesInc., Grand Island, N.Y.). The cells were cultured at 37° C. in ahumidified atmosphere with a 5% CO₂ content and kept in the exponentialgrowth phase by twice weekly subculturing. The cultures were tested formycoplasma infection using the MycoAlert Detection Kit (product numberLT07-118, Cambrex, Verviers, Belgium).

The cytotoxic effect of a two-day (48 hours) pretreatment of HT-29 cellswith 0 μM, 20 μM, 50 μM or 100 μM DHA or EPA on irradiation of the cellsat 0 Gy, Gy, 4 Gy or 6 Gy was examined in a 15-day clonogenicityexperiment.

To this end, the culture medium of the cells was replaced with mediumwhich contained the relevant concentrations (0 μM, 20 μM, 50 μM or 100μM) of DHA or EPA. Controls were cultured in medium without EPA andwithout DHA. The cells were cultured for 48 hours in the various media,and then irradiated with an individual radiation dose of 0 Gy (control),2 Gy, 4 Gy or 6 Gy in an X-ray 6 MV instrument. The cells were thendetached from the culture vessel by means of trypsinization (lxtrypsin-EDTA, Life Technologies Inc., Grand Island, N.Y.), resuspendedand counted. The cells were subsequently serially diluted according to astandard protocol and seeded in 100×20 mm cell culture dishes containing10 mL of cell culture medium in a cell count which leads to theformation of about 200 colonies. After a 14-day incubation at 37° C.,the vessels were washed with phosphate-buffered saline (PBS, LifeTechnologies Inc., Grand Island, N.Y.), fixed, and stained with a 0.5%crystal violet solution in methanol/glacial acetic acid (3:1, v/v). Thesurviving cell fraction was calculated with reference to the untreatedcontrols (S/S0).

The results (see FIG. 4) of the experiment indicate a synergistic effectof a dose of from 20 μM to 100 μM of the omega-3 fatty acids DHA and EPAwith irradiation of from 2 to 6 Gy (see FIG. 4).

Example 7 Investigation of the Influence of EPA and DHA on theIrradiation Sensitivity of Cancer Cell Lines In Vitro

Human cancer cell lines (HT-29; ATCC number HTB-38) are cultured inDulbecco's Modified Eagle's Medium (DMEM, product number D 5030, SigmaChemie AG, Buchs, Switzerland) supplemented with 10% heat-inactivatedfetal calf serum (FBS), 1 g/L D-glucose, 3.7 g/L sodium bicarbonate and0.1 g/L penicillin-streptomycin (all additives from Life TechnologiesInc., Grand Island, N.Y.). The cells are cultured at 37° C. in ahumidified atmosphere with a 5% CO₂ content and kept in the exponentialgrowth phase by twice weekly subculturing. The cultures are tested formycoplasma infection using the MycoAlert Detection Kit (product numberLT07-118, Cambrex, Verviers, Belgium).

The cytotoxic effect of treatment of the cells with DHA, EPA, MCTs andiron on irradiation of the cells at 0 Gy, 2 Gy, 4 Gy or 6 Gy is examinedin a 15-day clonogenicity experiment.

Firstly, the influence of 0 μM, 20 μM, 50 μM or 100 μM DHA or EPA in thecase of treatment of the cells (A) prior to the irradiation compared tothe treatment of the cells after the irradiation (B) is determined.Cells untreated with EPA or DHA, which are also irradiated, serve as acontrol (C).

In the case of the cells which are treated with EPA or DHA prior to theirradiation (A), the culture medium of the cells is replaced with mediumcontaining the relevant concentrations (0 μM, 20 μM, 50 μM or 100 μM) ofDHA or EPA. The cells are cultured for 48 hours in the medium, and thenirradiated with an individual radiation dose of 0 Gy (control), 2 Gy, 4Gy or 6 Gy in an X-ray 6 MV instrument.

In the case of cells which are treated with EPA or DHA after theirradiation (B) and in the case of the control cells (C), a media changeis carried out 48 hours prior to the irradiation; the cells receivenormal culture medium. After 48 hours, the cells are irradiated with anindividual radiation dose of 0 Gy (control), 2 Gy, 4 Gy or 6 Gy in anX-ray 6 MV instrument.

After the irradiation, the cells are then detached from the culturevessel by means of trypsinization (lx trypsin-EDTA, Life TechnologiesInc., Grand Island, N.Y.), resuspended and counted. The cells aresubsequently serially diluted according to a standard protocol andseeded in 100×20 mm cell culture dishes containing 10 mL of medium in acell count which leads to the formation of about 200 colonies. Cells ofgroups A and C are seeded in normal culture medium, and cells of group Bare seeded in medium containing the relevant concentrations (0 μM, 20μM, 50 μM or 100 μM) of DHA or EPA.

After 48 hours, all cells are subjected to a media change, after whichall cells are cultured in normal culture medium.

After a total of 14 days of incubation at 37° C., the vessels are washedwith phosphate-buffered saline (PBS, Life Technologies Inc., GrandIsland, N.Y.), fixed, and stained with a 0.5% crystal violet solution inmethanol/glacial acetic acid (3:1, v/v). The surviving cell fraction iscalculated with reference to the untreated controls (S/S0).

It is shown that, in the case of treatment with EPA or DHA prior to theirradiation (A), there is formation of fewer colonies with respect tothe untreated controls (C) and to the cells treated after theirradiation (B), and the colonies formed are smaller. The surviving cellfraction is also smaller.

The experiment is carried out analogously with further tumor cell lines(colorectal cancer cell lines, breast cancer cell lines and lung cancercell lines). In these cell lines too, there is a greater cytotoxiceffect of pretreatment with EPA or DHA compared to post treatment withEPA or DHA.

Example 8 Influence of Administration of Omegaven® on Efficacy andAdverse Effects of Irradiation In Vivo

In the first part of the experiment, the influence of Omegaven® on theefficacy of irradiation in female Balb/c nude mice (Elevage Janvier, LeGenest St Isle, France) is investigated. Animals aged between 6 and 8weeks and weighing about 25 g are used. After receipt, the animals areinjected subcutaneously with 4×10⁶ cells/0.1 mL of the human colorectalcancer cell line HT29, and kept in isolator cages for two weeks understandardized, defined pathogen-free conditions; autoclaved litter andfeed are used.

After the inoculation with tumor cells and the growth of the tumors, themice are divided up into the various experimental groups. The divisionis carried out such that comparable mean tumor volumes are present amongthe groups. Group A receives, 48 and 24 prior to the start of theirradiation, an intravenous infusion with Omegaven® in each case (2 mLper kg of body weight per day; corresponding to 60 μL of Omegaven® per200 μL of saline in the case of a weight of 30 g). The injection iscarried out via the tail vein. Animals of group B receive, in additionto the infusion with Omegaven® 48 hours and 24 hours, a further infusionwith Omegaven® three hours prior to the start of the irradiation.Animals of control group C receive, 48 hours and 24 hours prior to thestart of the irradiation, an intravenous infusion with Lipovenös® ineach case in an appropriate dose. Animals of control group D receive, 24hours and 48 hours after the start of the irradiation, an intravenousinfusion with Omegaven® in each case (2 mL per kg of body weight perday). The irradiation of the tumors is carried out by two-timeirradiation at 7.5 Gy.

Influence on the Efficacy of the Irradiation:

Tumor growth is determined by the measurement of the three orthogonaltumor diameters using a caliper by means of the formula

Tumor volume=4π/3×(length/2×width/2×height/2)

The measurement is carried out every two days. Changes in tumor volumeare calculated with reference to the initial tumor volume of an animal.

It is shown that animals of groups A and B have a lower mean tumorvolume compared to animals of groups C and D. A trend toward a reducedtumor volume in the animals of group B compared to group A is observed.

In the second part of the experiment, the influence of Omegaven® on theadverse effects of the irradiation is investigated. The female C57 blackmice used are kept as described above. The animals of group A receive,48 and 24 prior to the start of the irradiation, an intravenous infusionwith Omegaven® in each case (2 mL per kg of body weight per day;corresponding to 60 μL of Omegaven® per 200 μL of saline in the case ofa weight of 30 g). The injection is carried out via the tail vein.Animals of group B receive, in addition to the infusion with Omegaven®48 hours and 24 hours, a further infusion with Omegaven® three hoursprior to the start of the irradiation. Animals of control group Creceive, 48 hours and 24 hours prior to the start of the irradiation, anintravenous infusion with Lipovenös® in each case in an appropriatedose. Animals of control group D receive, 24 hours and 48 hours afterthe start of the irradiation, an intravenous infusion with Omegaven® ineach case (2 mL per kg of body weight per day). The irradiation of theanimals is carried out at an individual dose of 16.5 Gy. In thisconnection, the animals are shielded by lead plates such that the snoutof the animals is selectively irradiated.

After the irradiation, adverse effects which occur (reactions of theepidermis and mucosa, edemas, weight loss) are documented and comparedamong the groups. The parameters recorded comprise degree of swelling,degree of redness, scab formation.

It is shown that animals of groups A and B develop the adverse effectsof the chemotherapy less strongly than animals of group C. The extent ofthe adverse effects is lower than that observed in the case of theanimals of group D. The experiment shows a protective effect of theadministration of Omegaven®, which is particularly pronounced whenOmegaven® has already been administered prior to the irradiation.

1. A composition comprising a combination of the omega-3 fatty acidseicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for use inthe improvement of the efficacy of a chemotherapy or of a radiationtherapy and/or in the prevention or reduction of adverse effects causedby the chemotherapy or the radiation therapy in a patient who hasdeveloped cancer, wherein the composition is to be administered to thepatient not until from 48 to 24 hours prior to the start of a cycle ofthe chemotherapy or of the radiation therapy, wherein the compositioncontains from 1.0 g/100 mL to 7.0 g/100 mL EPA and from 1.0 g/100 mL to7.0 g/100 mL DHA.
 2. The composition for use as claimed in claim 1,wherein the adverse effects are selected from the group consisting ofgastrointestinal adverse effects, hematologic adverse effects, reductionin liver weight, neurotoxic adverse effects, adverse effects affectingthe heart, inflammatory adverse effects, weight loss, limited functionof the immune system, reduction of inflammations or a combinationthereof.
 3. The composition for use as claimed in claim 1, wherein thecancer is selected from the group consisting of solid tumors andnonsolid tumors, wherein the solid tumors are preferably selected fromthe group consisting of colorectal cancer, breast cancer, pancreaticcancer, liver cancer, lung cancer, and stomach cancer.
 4. Thecomposition for use as claimed in claim 1, wherein the chemotherapycomprises a chemotherapeutic selected from the group consisting of5-fluorouracil, gemcitabine, doxorubicin, paclitaxel, mitomycin,cyclophosphamide, epirubicin, arabinosylcytosine, tamoxifen, irinotecan,oxaliplatin, folinic acid, cisplatin, taxanes, vinca alkaloids,epipodophyllotoxins, synthetic alkaloids, cytarabine, nitrosourea,dacarbazine, fludarabine, ifosfamide, mitomycin C, tamoxifen or acombination thereof.
 5. The composition for use as claimed in claim 1,wherein the chemotherapy comprises 5-fluorouracil, wherein thechemotherapy is preferably FOLFOX or FOLFIRI.
 6. The composition for useas claimed in claim 1, wherein the radiation therapy is selected fromthe group consisting of teletherapy and brachytherapy.
 7. Thecomposition for use as claimed in claim 1, wherein the compositioncontains further preferred additives selected from the group consistingof medium-chain fatty acids and iron, or a combination thereof.
 8. Thecomposition for use as claimed in claim 1, wherein the compositioncontains from 1.0 g/100 mL to 4.0 g/100 mL EPA and/or from 1.0 g/100 mLto 4.0 g/100 mL DHA.
 9. (canceled)
 10. (canceled)
 11. The compositionfor use as claimed in claim 1, wherein the composition is alsoadditionally administered between 24 hours and 1 hour prior to the startof the cycle of the chemotherapy or radiation therapy, wherein thecomposition is preferably administered 3 hours prior to the start of acycle of the chemotherapy or of the radiation therapy.
 12. Thecomposition for use as claimed in claim 1, wherein the administration ofthe composition is repeated, wherein the composition is preferablyadministered 2 to 5 times.
 13. The composition for use as claimed inclaim 1, wherein the composition is administered prior to each cycle ofthe chemotherapy or radiation therapy.
 14. The composition for use asclaimed in claim 1, wherein from 5 mg to 250 mg of EPA per kilogram ofbody weight per day are administered, preferably wherein from 20 mg to80 mg of EPA per kilogram of body weight per day are administered, mostpreferably wherein from 40 mg to 60 mg of EPA per kilogram of bodyweight per day are administered and/or wherein from 5 mg to 250 mg ofDHA per kilogram of body weight per day are administered, preferablywherein from 20 mg to 80 mg of DHA per kilogram of body weight per dayare administered, most preferably wherein from 40 mg to 60 mg of DHA perkilogram of body weight per day are administered.
 15. The compositionfor use as claimed in claim 2, wherein the cancer is selected from thegroup consisting of solid tumors and nonsolid tumors, wherein the solidtumors are preferably selected from the group consisting of colorectalcancer, breast cancer, pancreatic cancer, liver cancer, lung cancer, andstomach cancer.
 16. The composition for use as claimed in claim 2,wherein the chemotherapy comprises a chemotherapeutic selected from thegroup consisting of 5-fluorouracil, gemcitabine, doxorubicin,paclitaxel, mitomycin, cyclophosphamide, epirubicin, arabinosylcytosine,tamoxifen, irinotecan, oxaliplatin, folinic acid, cisplatin, taxanes,vinca alkaloids, epipodophyllotoxins, synthetic alkaloids, cytarabine,nitrosourea, dacarbazine, fludarabine, ifosfamide, mitomycin C,tamoxifen or a combination thereof.
 17. The composition for use asclaimed in claim 3, wherein the chemotherapy comprises achemotherapeutic selected from the group consisting of 5-fluorouracil,gemcitabine, doxorubicin, paclitaxel, mitomycin, cyclophosphamide,epirubicin, arabinosylcytosine, tamoxifen, irinotecan, oxaliplatin,folinic acid, cisplatin, taxanes, vinca alkaloids, epipodophyllotoxins,synthetic alkaloids, cytarabine, nitrosourea, dacarbazine, fludarabine,ifosfamide, mitomycin C, tamoxifen or a combination thereof.
 18. Thecomposition for use as claimed in claim 2, wherein the chemotherapycomprises 5-fluorouracil, wherein the chemotherapy is preferably FOLFOXor FOLFIRI.
 19. The composition for use as claimed in claim 3, whereinthe chemotherapy comprises 5-fluorouracil, wherein the chemotherapy ispreferably FOLFOX or FOLFIRI.
 20. The composition for use as claimed inclaim 4, wherein the chemotherapy comprises 5-fluorouracil, wherein thechemotherapy is preferably FOLFOX or FOLFIRI.
 21. The composition foruse as claimed in claim 2, wherein the radiation therapy is selectedfrom the group consisting of teletherapy and brachytherapy.
 22. Thecomposition for use as claimed in claim 3, wherein the radiation therapyis selected from the group consisting of teletherapy and brachytherapy.